Prf1

..This is the first study illustrating an NK cell-mediated immunopathological outcome to an acute viral infection...

..The data suggest that activated mast cells contribute, via secreted gzmB, to cell death, increased vascular permeability, leukocyte extravasation and subsequent inflammatory processes in affected tissues...

..These results reflect a critical role for NK cells and gammadeltaTCR+ T cells in innate immune surveillance of B cell lymphomas, mediated by as yet undetermined pathway(s) of tumor recognition...

..In addition, perforin-mediated anti-recipient cytotoxicity appears to play an important role in the kinetics of GVHD pathophysiology, but is not required for GVHD-associated tissue damage...

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..The mice fail to clear lymphocytic choriomeningitis virus and they eliminate fibrosarcoma tumour cells with reduced efficiency. Perforin is therefore a key effector molecule for T-cell- and natural killer-cell-mediated cytolysis...

..This study is the first to describe the concomitant maturation of NK cell effector function with surface phenotype in vivo and implies an important defense role for NK cell TRAIL in the developing immune system...

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..These data suggest that resting murine NK cells are minimally cytotoxic because of a block in perforin and granzyme B mRNA translation that is released by NK cell activation...

..Depletion of NK subsets resulted in greater numbers of metastases than observed in perforin-deficient mice, suggesting that perforin-independent effector functions of NK cells may also contribute to protection from tumor metastasis...

..We conclude that perforin-dependent effector cells such as cytotoxic T cells, gammadelta T cells, and natural killer cells may play a role in axon damage that is dependent upon but separable from demyelination...

..These results demonstrate the role of direct effector function of Ag-specific CD4 T cells in preventing severe WNV disease...

..This is the first description of an antitumor function for NKT cells in the absence of exogenously administered potent stimulators such as IL-12 or alpha-galactosylceramide...

..Thus, perforin and IFN-gamma regulate distinct elements of CD8+ T cell homeostasis independently of their role as antimicrobial effector molecules...

Perforin (pfp) and interferon-gamma (IFN-gamma) together in C57BL/6 (B6) and BALB/c mouse strains provided optimal protection in 3 separate tumor models controlled by innate immunity...

..We conclude that IL-21 immunotherapy warrants clinical evaluation as a potential treatment for cancer...

..TRAIL gene-targeted mice were also more sensitive to the chemical carcinogen methylcholanthrene. These results substantiated TRAIL as an important natural effector molecule used in the host defense against transformed cells...

..of the acute phase of murine cytomegalovirus (MCMV) infection and have been reported to utilize perforin (Pfp)- and gamma interferon (IFN-gamma)-dependent effector mechanisms in an organ-specific manner to regulate MCMV ..

..we describe spontaneous tumor development in gene-targeted mice lacking interferon (IFN)-gamma and/or perforin (pfp), or the immunoregulatory cytokines, interleukin (IL)-12, IL-18, and tumor necrosis factor (TNF)...

..These results may explain why the Cmv-lr locus, which maps closely to genes regulating NK cell cytotoxic function, confers an NK cell-dependent resistance to MCMV infection in the spleen but not in the liver...

..These studies provide insight into the pathophysiology of HLH, and provide new targets for specific therapeutic intervention in this fatal disorder...

..These studies implicate perforin release by CD8(+) T cells as a potential mechanism by which neurologic deficits are induced after demyelination...

..These results suggest that perforin is a key mediator of axon injury and lend additional support to the hypothesis that CD8 T cells are primarily responsible for axon damage in multiple sclerosis...

..This suggests that gzmA and B are critical for Tc/NK granule- mediated nucleolysis, with gzmB being the main contributor, while target cell lysis is due solely to perforin and independent of both proteases...

..These data not only confirmed the primary role of perforin but simultaneously revealed a major contribution of a perforin-independent Fas-mediated pathway in antigen-specific cytolysis...

..We conclude that perforin-less -/- mice retain and express the Fas lytic pathway as expressed in vitro but that this pathway is insufficient to clear an LCMV infection in vivo...

..Thus, two complementary, specific cytotoxic mechanisms are functional in CTLs, one based on the secretion of lytic proteins and one which depends on cell-surface ligand-receptor interaction...

..All cytotoxicity observed was due to either of these mechanisms, and no third mechanism was detected. Thus, the perforin- and Fas-based mechanisms may account for all T cell-mediated cytotoxicity in short-term in vitro assays...

Genomic clones encompassing the entire coding region of the mouse lymphocyte pore-forming protein gene (Pfp) have been isolated and used to determine its intron-exon organization...

..However, in the absence of perforin chronic inflammation of the islets can lead to diabetogenic beta cell loss by less efficient secondary effector mechanisms...

..These developmental changes suggested that IL-21 functions to induce the terminal differentiation of mouse NK cells, resulting in heightened NK cell-mediated cytotoxicity and immune surveillance...

..Here we showed that perforin (Prf1) and granzymes (Gzms) have distinct roles in defensive immunity and immunopathology in a well-established model of ..

..We conclude that perforin is a crucial effector molecule in T cell- and NK cell-mediated cytolysis. However, alternative perforin-independent lytic mechanisms also exist...

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..Unlike oligodendrocytes, astrocytes were killed by FasL in vitro. It remains to be established whether this latter finding explains the different disease course of lpr and gld mice compared to wild-type and perforin knockout mice...

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..These results establish that both gzmA and gzmB are indispensable effector molecules acting in concert with perforin in granule exocytosis-mediated host defense against natural viral pathogens...

..Dependence on perforin function was demonstrated for the cytotoxicity of these effectors in vitro and for the ability of these effectors to reject a variety of tumors in vivo...

..These studies demonstrate a novel role for perforin in homeostatic regulation of the immune response...

..cruzi strain. This protocol led to acute phase survival in both wild-type and perforin null (pfp(-/-)) mice lineages...

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..This ensures that CTLs can eliminate those target cells that have compromised apoptotic potential due to overexpression of Bcl-2...

..In addition, the revelation that TNF-alpha is the principal mediator of RSV-induced illness means that administration of TNF receptor antagonists, in combination with antiviral therapy, may be an effective method to treat RSV infections...

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..These results suggest that rapid transfer of T. gondii from infected DC to effector NK cells may contribute to the parasite's sequestration and shielding from immune recognition shortly after infection...

..These findings indicate that TNF/TNFR2 interactions facilitate generation of FasL-dependent CTL effector pathways that play an important role in in vivo antiviral-immune responses in the liver...

..Our model is that host lymphoid cells in response to a tumour increase NO synthesis, which in turn causes enhanced Fas expression in the tumour...

..Thus, iNKT cells regulate the survival of CD8(+) DCs through a mechanism that does not appear to involve direct cell killing...

..To our knowledge, this report is the first demonstrating a role for IFN-gamma-producing DC from Peyer's patches in the development of Ag-specific IEL population and their trafficking to the gut epithelium...

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..We show that in the absence of 2B4 signaling, activated NK cells have defective cytotoxicity and proliferation because of fratricide and not due to the absence of a 2B4-dependent activation signal...

..Overall, these data indicate the general role that IL-23 plays in suppressing natural or cytokine-induced innate immunity, promoting tumor development and metastases independently of IL-17A...

..Their suppressor function is dependent on direct contact, partially dependent on perforin 1 (Prf1), but independent of granzyme B (GzmB), and surprisingly, Foxp3...

..Therefore, unlike NK cells, which rely mostly on perforin/granzyme-mediated mechanisms, the Ag-specific cytotoxicity of iNKT cells in vivo is largely restricted to the CD95/CD178 pathway...

..Collectively, these findings suggest that IL-21 therapy may work optimally against tumors that can elicit a NKG2D-mediated immune response...

..In this study we examined the role of perforin (pfp), a key molecule of the cytotoxic death pathway that is expressed mainly in CD8+ T cells, for the pathogenesis of ..

..Thus, our data also imply that adoptive transfer of tumor-specific CD8 T cells might synergize with radiation therapy or chemotherapy in the elimination of solid tumors in vivo...

..These results indicate that single Ag-specific CD8+ T cells derived from PO mice can mediate antilisterial immunity by a mechanism that is independent of CD95 or IFN-gamma, but requires TNF-alpha...

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..In addition, we confirm the existence of two types of mouse perforin mRNA that differ in their 5' untranslated regions, and show evidence that both mRNA are translated in vivo with similar efficiencies...

..In contrast, perforin did not influence T cell proliferation. Therefore, perforin is an essential immunoregulatory molecule that may be required for the induction of transplantation tolerance...

..These results suggest that the presence of excessive IL-2 during the activation of naive CD8+ T cells, while promoting cell cycling initially, may compromise long-term immunity...

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..pneumoniae. The higher sensitivity of IFN-gammaR-/- mice to C. pneumoniae compared with that of SCID or recombination-activating gene-1-/- mice suggested a relevant protective role of IFN-gamma-dependent innate mechanisms of protection...

..Th1 cells have recently been shown to be regulated by Fas and we speculate that Fas-mediated mechanisms are involved in the regulation of both Th1 and T1 populations of T cells...

..genes involved in oncogenesis (Gli, Myb, Tra-1), proviral integration (Emv-25), and immune responses (Ifg, Ifgr, Pfp). The linkage map spans much of the chromosome and covers a region of the mouse genome with few molecular markers...

..There was no significant difference between the infectious viral titers isolated from the eyes of PKO and wild-type mice. Our findings show that perforin is important in the pathogenesis of HSK...

..These data show that TGFbeta-activated CD8+ T cells mediate antigen-specific, APC-focused patterns of suppression in vitro and in vivo...

..Therefore, NOD8.3 T-cells use both perforin and Fas pathways to kill beta-cells and the surprising blockade of NOD8.3 T-cell-mediated beta-cell death by SOCS-1 overexpression may be due in part to reduced target cell recognition...

..We conclude that cathepsin B is not essential for protection of cytotoxic lymphocytes from the toxic effects of their secreted perforin...

..Thus, antibody is essential, but CD4 or CD8 T cells are not required for recovery from secondary poxvirus infection...

..The results are compatible with a model of a defective activation-induced cell death (AICD) pathway, controlled by perforin, accounting for the increased expansion of alloreactive pko T cells...

..Although the mechanism responsible for this observation is yet to be established, the lower virus titres found in these mice indicate that the role of cytolytic effector molecules in antiviral immunity needs to be re-evaluated...

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..We think that the recognition and killing of target cells by NK cells represents an important pathway for the generation of robust CD8+ T and humoral responses that may be exploited for vaccine development...

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..Also, CTL-mediated death caused as much FA release as death by disruption of cells by freeze-thawing. The released oleic acid may be sufficient to promote secondary apoptotic responses after CTL-induced trauma...

..Our results indicate that protein disulfide isomerases, in the ER or elsewhere, may protect T cells from their own perforin...

..Our results uncover a specific role of MEF in the development and function of NK cells and in innate immunity...

..These observations identify caspase-8 and the BH3-only proteins Bid and Bim as potential therapeutic targets for treatment of inflammatory liver diseases...

..These results demonstrate that PEA induces liver damage not only by protein synthesis inhibition but also by TNF- and perforin-dependent, Fas-independent, apoptotic signals...

..Finally, we show that production of IFN-gamma, but not perforin or TNF-alpha, by the donor lymphocytes is critical for control of autochthonous brain tumors...

..The observation that a defect in DC apoptosis can independently lead to autoimmunity is consistent with a central role for these cells in maintaining immune self-tolerance...

..This is the first report in which a strong dependence upon the cytolytic activity of host CD8+ T cells has been shown to be important in a parasite infection...

..As expression of the Bcl-2 family members controls susceptibility to apoptosis, this finding may provide a molecular basis for the survival of anergic cells under conditions of prolonged antigen stimulation...

..Together these results suggest that donor cdd CD8+ T cells expand continuously and cause lethal GVHD, and that both perforin and FasL are required for the contraction of allo-reactive CD8+ T cells...

..Thus, the defect in NK precursor cell maturation was not intrinsic to the NK precursor cells but was dependent upon the tissue environment. In summary, IL-11 signaling is required for decidual-specific maturation of NK cells...

..Thus, perforin-dependent early AICD appears to require activation of caspase 3, but not caspases 8 or 9. As perforin has no intrinsic catalytic abilities, we propose that it releases some endogenous activity that can activate caspase 3...

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..The data further imply that IFN-gamma plays a crucial role in pathogenesis by regulating the balance between virus replication in oligodendrocytes, CD8(+) T cell effector function, and demyelination...

..These findings delineate a Qa-1-dependent T cell-T cell inhibitory interaction that prevents the pathogenic expansion of autoreactive CD4 T cell populations and consequent autoimmune disease...

..Wild-type (WT), perforin/recombinase activating gene-2 knockout (pfp/RAG-2 KO), and common gamma-chain (gammac)/RAG-2 KO mice received a right facial nerve axotomy...

..Thus, increasing the number of memory CD8(+) T cells can overcome diminished per-cell protective immunity in the absence of perforin...

..Thus, perforin was essential for resistance to secondary LCMV infection, and, in the absence of perforin, vaccination resulted in lethal disease mediated by dysregulated CD8(+) T cell expansion and cytokine production...

..We conclude that selection of viral CTL escape variants reflects coordinate action between the tightly controlled perforin/granzyme pathway and the more promiscuous Fas/FasL pathway...

..Together with previous graft survival studies, these results indicate that the granule-associated cytotoxic mechanisms of T cells are not the effectors of T-cell-mediated allograft rejection...

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..These data indicate that PD-1 ligation down-regulates GVHD through modulation of IFN-gamma production and suggest a novel therapeutic target for inhibiting GVHD lethality...

..Our data support the 'threshold model' of AICD by demonstrating that AICD is controlled by the strength of T cell activation...

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..This proposal focuses clearly on a pivotal immune control mechanism that will influence many current and future immunotherapies. ..

..This project will lead to better understanding of how cytotoxic function regulates the immune response and lead to improved therapies for patients with HLH and perhaps many other immunopathologic disorders. ..

..This project will lead to better understanding of how cytotoxic function regulates the immune response and lead to improved therapies for patients with HLH and perhaps many other immunopathologic disorders. ..

..These studies will lead to improved strategies for re-establishing immune privilege of corneal transplants and offsetting the untoward effects of allergic diseases on the fate of corneal transplants. ..

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..All three of these aims will be addressed in a well-characterized mouse model of penetrating keratoplasty. ..

..Both strategies procure antigen-specific suppression of host immune responses and should prove useful in preventing corneal graft rejection. ..

..The main objective of this research is to more precisely define the contribution of HBV-specific CTL to viral clearance and pathogenesis by providing the first comprehensive analysis of these cells in situ. ..

..g., corneal transplantation). In some cases, it may be desirable to abrogate immune privilege to promote the immune-rejection of sight- and life-threatening ocular neoplasms. ..

..My near term career path will involve ongoing basic research and study in order to improve my ultimate scientific productivity. ..

..The main objective of this research is to define the immunologic parameters that contribute to viral clearance versus persistence in the CNS and foster approaches that tip the balance in favor of clearance. ..

..These studies will lead to improved strategies for re-establishing immune privilege of corneal transplants and offsetting the untoward effects of allergic diseases on the fate of corneal transplants. ..

..This project will lead to better understanding of how cytotoxic function regulates the immune response and lead to improved therapies for patients with HLH and perhaps many other immunopathologic disorders. ..

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..This project will lead to better understanding of how cytotoxic function regulates the immune response and lead to improved therapies for patients with HLH and perhaps many other immunopathologic disorders. ..

..The fourth aim will evaluate the therapeutic efficacy of a monoclonal antibody directed against human CD54 in controlling liver metastases in a nude mouse model of uveal melanoma. ..

..Importantly, we have found that treatment with an FDA-approved drug protects neurons and cognitive function without altering the ability of the immune system to clear the virus from the brain. ..

..Understanding how the immune system supports hematopoiesis is needed to develop strategies for the prevention and treatment of pancytopenia in AIDS patients. ..

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..The long range goals of this project are to understand immune regulatory processes in the eye and to manipulate such processes to reduce immune-mediated injury and corneal graft rejection...

..The results from these investigations should provide important insights into the immunobiology of corneal allografts and the feasibility of specific immunological strategies for promoting corneal allograft survival...

..g., corneal transplantation). In some cases, it may be desirable to abrogate immune privilege to promote the immune-rejection of sight- and life-threatening ocular neoplasms. ..

..g., corneal transplantation) or abrogate immune privilege to protect against sight- and life-threatening neoplasms. ..